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      Case Report: A Chinese Family of Woodhouse-Sakati Syndrome With Diabetes Mellitus, With a Novel Biallelic Deletion Mutation of the DCAF17 Gene


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          Woodhouse–Sakati syndrome (WSS) (OMIM#241080) is a rare multi-system autosomal recessive disease with homozygous mutation of the DCAF17 gene. The main features of WSS include diabetes, hypogonadism, alopecia, deafness, intellectual disability and progressive extrapyramidal syndrome. We identified a WSS family with a novel DCAF17 gene mutation type in China. Two unconsanguineous siblings from the Chinese Han family exhibiting signs and symptoms of Woodhouse-Sakati syndrome were presented for evaluation. Whole-exome sequencing revealed a homozygous deletion NM_025000.4:c.1488_1489delAG in the DCAF17 gene, which resulted in a frameshift mutation that led to stop codon formation. We found that the two patients exhibited low insulin and C-peptide release after glucose stimulation by insulin and C-peptide release tests. These findings indicate that the DCAF17 gene mutation may cause pancreatic β cell functional impairment and contribute to the development of diabetes.

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          Most cited references13

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          Phenolyzer: phenotype-based prioritization of candidate genes for human diseases.

          Prior biological knowledge and phenotype information may help to identify disease genes from human whole-genome and whole-exome sequencing studies. We developed Phenolyzer (http://phenolyzer.usc.edu), a tool that uses prior information to implicate genes involved in diseases. Phenolyzer exhibits superior performance over competing methods for prioritizing Mendelian and complex disease genes, based on disease or phenotype terms entered as free text.
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            ClinPred: Prediction Tool to Identify Disease-Relevant Nonsynonymous Single-Nucleotide Variants

            Advances in high-throughput DNA sequencing have revolutionized the discovery of variants in the human genome; however, interpreting the phenotypic effects of those variants is still a challenge. While several computational approaches to predict variant impact are available, their accuracy is limited and further improvement is needed. Here, we introduce ClinPred, an efficient tool for identifying disease-relevant nonsynonymous variants. Our predictor incorporates two machine learning algorithms that use existing pathogenicity scores and, notably, benefits from inclusion of normal population allele frequency from the gnomAD database as an input feature. Another major strength of our approach is the use of ClinVar—a rapidly growing database that allows selection of confidently annotated disease-causing variants—as a training set. Compared to other methods, ClinPred showed superior accuracy for predicting pathogenicity, achieving the highest area under the curve (AUC) score and increasing both the specificity and sensitivity in different test datasets. It also obtained the best performance according to various other metrics. Moreover, ClinPred performance remained robust with respect to disease type (cancer or rare disease) and mechanism (gain or loss of function). Importantly, we observed that adding allele frequency as a predictive feature—as opposed to setting fixed allele frequency cutoffs—boosts the performance of prediction. We provide pre-computed ClinPred scores for all possible human missense variants in the exome to facilitate its use by the community.
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              Mutations in C2orf37, encoding a nucleolar protein, cause hypogonadism, alopecia, diabetes mellitus, mental retardation, and extrapyramidal syndrome.

              Hypogonadism, alopecia, diabetes mellitus, mental retardation, and extrapyramidal syndrome (also referenced as Woodhouse-Sakati syndrome) is a rare autosomal recessive multisystemic disorder. We have identified a founder mutation consisting of a single base-pair deletion in C2orf37 in eight families of Saudi origin. Three other loss-of-function mutations were subsequently discovered in patients of different ethnicities. The gene encodes a nucleolar protein of unknown function, and the cellular phenotype observed in patient lymphoblasts implicates a role for the nucleolus in the pathogenesis of this disease. Our findings expand the list of human disorders linked to the nucleolus and further highlight the developmental and/or maintenance functions of this organelle.

                Author and article information

                Front Endocrinol (Lausanne)
                Front Endocrinol (Lausanne)
                Front. Endocrinol.
                Frontiers in Endocrinology
                Frontiers Media S.A.
                23 December 2021
                : 12
                [1] 1 Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China
                [2] 2 Key Laboratory of Respiratory Diseases, National Ministry of Health of the People’s Republic of China and National Clinical Research Center for Respiratory Disease , Wuhan, China
                [3] 3 Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China
                [4] 4 Hubei Provincial Clinical Research Center for Diabetes and Metabolic Disorders , Wuhan, China
                [5] 5 Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China
                [6] 6 Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China
                Author notes

                Edited by: Ming Liu, Tianjin Medical University General Hospital, China

                Reviewed by: Rabia Habib, COMSATS University, Pakistan; Suleyman Nahit Sendur, Hacettepe University, Turkey

                *Correspondence: Huiqing Li, lhqing5@ 123456126.com

                †These authors have contributed equally to this work and share first authorship

                This article was submitted to Clinical Diabetes, a section of the journal Frontiers in Endocrinology

                Copyright © 2021 Zhou, Shi, Zheng, Chen, Wang, Xiao, Cui, Qiu, Zhu and Li

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 3, Tables: 1, Equations: 0, References: 13, Pages: 6, Words: 2837
                Funded by: National Natural Science Foundation of China , doi 10.13039/501100001809;
                Case Report

                Endocrinology & Diabetes
                woodhouse–sakati syndrome,diabetes,intellectual disability,alopecia,hypogonadism


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